A phase 2 randomized trial to evaluate the impact of a supervised exercise program on cardiotoxicity at 3 months in patients with HER2 overexpressing breast cancer undergoing adjuvant treatment by trastuzumab: design of the CARDAPAC study

Abstract

BackgroundThe overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer is a poor prognosis. Trastuzumab improves overall survival but is associated with cardiotoxicity, especially a decline in left ventricular ejection fraction (LVEF). In addition, chemotherapy and radiotherapy increase fatigue and pain, decrease physical capacity and health-related quality of life. To date, no study has evaluated the benefits of physical activity on the side effects of treatment in patients with HER2 positive breast cancer. The aim of this study is to evaluate the impact of 3 months’ exercise intervention on myocardial function and in particular on the rate of cardiotoxicity.MethodsThis multicenter, randomized clinical trial will include 112 patients treated by adjuvant trastuzumab for HER2 positive breast cancer to investigate the effects of a 3 months’ supervised exercise program (intermittent exercise, combining moderate and high intensities; 55 minutes duration, 3 times per week), on the rate of cardiotoxicity [defined by either a decrease of the LVEF under 50% or an absolute drop of LVEF of 10%] between baseline and at 3 months and on strength, aerobic capacity, metabolic, inflammatory and hormonal parameters. Health-related quality of life, fatigue, pain and level of physical activity will also be assessed. Participants are randomly allocated to one of the two groups (“training group” vs “standard oncological care”). Performance-based and self-reported outcomes are assessed at baseline, at the end of supervised exercise program and at six months follow-up.DiscussionAlthough physical exercise is recommended to reduce the side effects of adjuvant treatments in breast cancer patients, no randomized study has been conducted to assess the benefits of a physical training program in patients with HER2 overexpressing breast cancer. Cardiac toxicity of trastuzumab may be minimized with an exercise program combining high and moderate intensities. This type of program may be safe, feasible and effective but also increase cardiorespiratory fitness and improve health-related quality of life. If these benefits are confirmed, this exercise intervention could be systematically proposed to patients during the course of treatment by trastuzumab in addition to standard oncological care.Trial registrationNational Clinical Trials Number (NCT02433067); Registration 28 april 2015.

Molecular profiling for precision cancer therapies

“…The incidence of actionable genome aberrations is low overall and highly variable across tumor types, necessitating the testing of large numbers of tumors with significant use of resources. In the specific case of NTRK fusions, a diagnostic algorithm based on the incidence by tumor type and NTRK expression by IHC testing has been proposed as a more efficient detection strategy in routine practice [102][103][104][105].…”

Cardiac Toxicity of HER-2 Targeted Regimens

“…80 The CARDAPAC study (NCT02433067) is a phase II multicenter randomized trial of 112 HER2 breast cancer patients undergoing adjuvant treatment with trastuzumab, which is looking at the impact of a 3-month supervised exercise program with moderate and high intensity activity on cardiotoxicity (defined as a decrease of LVEF under 50%, or an absolute drop of LVEF 10% at baseline and at 3 months). 86 In regard to patients also receiving radiation therapy, a study is being conducted looking at breathhold techniques during treatments to reduce cardiac toxicity, as demonstrated by cardiac MRI at 12 months (NCT02052102). 87 Finally, from an imaging perspective, a double-blinded, prospective observational study is being conducted comparing cardiac MRI with MUGA scans in patients receiving trastuzumab in regard to LVEF assessment and LV volumes, and also comparing serial biomarker levels with changes in cardiac structure and function.…”

Physical exercise program, a strategy to prevent cardiotoxicity in early breast cancer: A literature review

“…Given the few studies and convincing results on the impact of exercise on the cardiotoxicity in breast cancer and especially in HER2 breast cancer, a randomized trial is ongoing to evaluate the impact of a supervised, intermittent and individualized exercise program, which consists of three 55-minute exercise sessions on cycloergometer a week for 12 weeks, on cardiotoxicity in patients with HER2-overexpressing breast cancer receiving adjuvant therapy with trastuzumab (Jacquinot et al, 2017). The data from this study should allow to verify whether the chronic intermittent exercise improves the LVEF or prevents its decrease, consequently decreases the cardiotoxicity and contributes to increase the functional capacities of patients.…”

“…Breast cancer is the most common cancer among women in the world, as in the European Union and France (Jemal et al, 2011). In recent years, adjuvant chemotherapy has been reported to decrease of 30 to 40% the risk of breast cancer mortality (Early Breast Cancer Trialists' Collaborative Group, 2012).…”